Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of transcription factors regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the transcription factor Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital 2-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell-cycle, fatty acid oxidation and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.
Sequencing data have been deposited in GEO under accession code GSE164889.
Transcriptional regulation of neural stem cell expansion in adult hippocampusNCBI Gene Expression Omnibus, GSE164889.
- J Tiago Gonçalves
- Amar Sahay
Animal experimentation: Animals were handled and experiments were conducted in accordance with procedures approved by the Institutional Animal Care and Use Committee (IACUC) at the Massachusetts General Hospital (2011N000084 ) and Albert Einstein College of Medicine in accordance with NIH guidelines.
- Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States
© 2022, Guo et al.
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The locus coeruleus (LC) houses the vast majority of noradrenergic neurons in the brain and regulates many fundamental functions including fight and flight response, attention control, and sleep/wake cycles. While efferent projections of the LC have been extensively investigated, little is known about its local circuit organization. Here, we performed large-scale multi-patch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions. LC noradrenergic neurons are diverse and could be classified into two major morpho-electric types. While fast excitatory synaptic transmission among LC noradrenergic neurons was not observed in our preparation, these mature LC neurons connected via gap junction at a rate similar to their early developmental stage and comparable to other brain regions. Most electrical connections form between dendrites and are restricted to narrowly spaced pairs or small clusters of neurons of the same type. In addition, more than two electrically coupled cell pairs were often identified across a cohort of neurons from individual multi-cell recording sets that followed a chain-like organizational pattern. The assembly of LC noradrenergic neurons thus follows a spatial and cell type-specific wiring principle that may be imposed by a unique chain-like rule.
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